Drug-nutrient interactions are of increasing concern as it has been estimated that 15 million Americans consume dietary supplements concurrently with prescription medications. Vitamin E has antioxidant benefits and is generally considered to be non-toxic even in relatively high doses (>1000 IU). Of potential importance are recently published intervention studies that have reported adverse effects of vitamin E, which may be directly related to its hepatic metabolism. Although vitamin E itself may not have adverse effects, our data suggest that a-tocopherol up-regulates xenobiotic metabolism, specifically cytochrome P450 3A (CYP 3A), the major CYP in human liver and intestine that is also the predominant enzyme involved in the metabolism of >50% of therapeutic drugs. Our long-term goal is to further elucidate the pathways involved in vitamin E regulation in order that vitamin E supplements may be used with optimal benefits in maintaining human health. The objective of this research is to define hepatic pathways for a-tocopherol catabolism and its disposition, as well as to specifically address a-tocopherol interactions with pharmacologic agents and their metabolizing systems. The central hypothesis of these studies is that pharmacologic amounts of a-tocopherol alter hepatic xenobiotic catabolism and excretion pathways that simultaneously prevent "excess" hepatic vitamin E accumulation. Our rationale for these studies is that their successful completion will allow formulation of public health recommendations using evidence-based knowledge of vitamin E interactions and potential interference with other pharmacologic agents and xenobiotics. We propose to: Aim 1. Define the intracellular pathway for a-tocopherol metabolism. Aim 2. Define how a-tocopherol modulates hepatic cytochrome P450 enzymes (CYPs) involved in the metabolism of therapeutic drugs. Aim 3. Determine the ability of a-tocopherol to modulate hepatic transport proteins known to be involved in the biliary excretion of a-tocopherol and/or therapeutic drugs. Aim 4. Determine alterations by a-tocopherol on other vitamin E's metabolism. The proposed research is innovative because it will challenge the current paradigm that a-tocopherol acts solely as an antioxidant. Our studies will demonstrate how a-tocopherol alters hepatic xenobiotic metabolism. We believe these studies are critical to our understanding of a-tocopherol actions, particularly in light of recent reports of adverse drug-vitamin E interactions. We believe that our findings may well have a significant impact on current self-medication practices of the millions of Americans currently taking prescription drugs and vitamin E supplements. [unreadable] [unreadable]